Title: Regulation of androgen receptor-dependent transcription by coactivator MED1 is mediated through a newly discovered noncanonical binding motif
Authors: Jin, Feng ×
Claessens, Frank
Fondell, Joseph D #
Issue Date: Jan-2012
Publisher: American Society for Biochemistry and Molecular Biology
Series Title: Journal of Biological Chemistry vol:287 issue:2 pages:858-70
Article number: 10.1074/jbc.M111.304519
Abstract: Nuclear receptor (NR) activation by cognate ligand generally involves allosteric realignment of C-terminal α-helices thus generating a binding surface for coactivators containing canonical LXXLL α-helical motifs. The androgen receptor (AR) is uncommon among NRs in that ligand triggers an intramolecular interaction between its N- and C-terminal domains (termed the N/C interaction) and that coactivators can alternatively bind to surfaces in the AR N-terminal or hinge regions. The evolutionary conserved Mediator complex plays a key coregulatory role in steroid hormone-dependent transcription and is chiefly targeted to NRs via the LXXLL-containing MED1 subunit. Whereas MED1 has been demonstrated to serve as a key transcriptional coactivator for AR, the mechanisms by which AR recruits MED1 have remained unclear. Here we show that MED1 binds to a distinct AR N-terminal region termed transactivation unit-1 (Tau-1) via two newly discovered noncanonical α-helical motifs located between MED1 residues 505 and 537. Neither of the two MED1 LXXLL motifs is required for AR binding, whereas loss of the intramolecular AR N/C interaction decreases MED1 binding. We further demonstrate that mitogen-activated protein kinase phosphorylation of MED1 enhances the AR-MED1 interaction in prostate cancer cells. In sum, our findings reveal a novel AR-coactivator binding mechanism that may have clinical implications for AR activity in prostate cancer.
ISSN: 0021-9258
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Gerontology and Geriatrics
Laboratory of Molecular Endocrinology
× corresponding author
# (joint) last author

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